tbuckley/cabot-search huggingface dataset:
Reevaluating the Role of Progesterone in Ovarian Cancer: Is Progesterone Always Protective?
Authors: Laura J Mauro, Angela Spartz, Julia R Austin, Carol A Lange
Journal: Endocrine Reviews (2023)

Abstract Ovarian cancer (OC) represents a collection of rare but lethal gynecologic cancers where the difficulty of early detection due to an often-subtle range of abdominal symptoms contributes to high fatality rates. With the exception of BRCA1/2 mutation carriers, OC most often manifests as a post-menopausal disease, a time in which the ovaries regress and circulating reproductive hormones diminish. Progesterone is thought to be a “protective” hormone that counters the proliferative actions of estrogen, as can be observed in the uterus or breast. Like other steroid hormone receptor family members, the transcriptional activity of the nuclear progesterone receptor (nPR) may be ligand dependent or independent and is fully integrated with other ubiquitous cell signaling pathways often altered in cancers. Emerging evidence in OC models challenges the singular protective role of progesterone/nPR. Herein, we integrate the historical perspective of progesterone on OC development and progression with exciting new research findings and critical interpretations to help paint a broader picture of the role of progesterone and nPR signaling in OC. We hope to alleviate some of the controversy around the role of progesterone and give insight into the importance of nPR actions in disease progression. A new perspective on the role of progesterone and nPR signaling integration will raise awareness to the complexity of nPRs and nPR-driven gene regulation in OC, help to reveal novel biomarkers, and lend critical knowledge for the development of better therapeutic strategies.
Eyelid Papilloma
Authors: Chun-Chieh Lai, Wan-Ju Annabelle Lee
Journal: Ophthalmology (2023)

A 69-year-old immunocompetent woman visited the ophthalmology clinic with a pink peduncular mass on the left lower eyelid margin, which was present for > 10 days. On examination, a 2 × 2-mm pink peduncular mass was observed on the left lower lid (A, asterisk). No history of papilloma, human papillomavirus infection vaccination (HPV), or eye injury was reported. The patient declined treatment for papilloma, including oral medications. She subsequently obtained the HPV 9-valent vaccine on her own accord, and after 2 doses of vaccine, (B) the papilloma spontaneously resolved within 2 months. (Magnified version of Figure A-B is available online at www.aaojournal.org).
Insulin Sensitivity and β-Cell Function During Early and Late Pregnancy in Women With and Without Gestational Diabetes Mellitus
Authors: Bettina Mittendorfer, Bruce W. Patterson, Debra Haire-Joshu, Alison G. Cahill, W. Todd Cade, Richard I. Stein, Samuel Klein
Journal: Diabetes Care (2023)

To evaluate the metabolic alterations associated with gestational diabetes mellitus (GDM) in women with overweight or obesity.We compared fasting and postprandial plasma glucose and free fatty acid (FFA) concentrations, insulin sensitivity (IS; Matsuda index), and β-cell function (i.e., β-cell responsiveness to glucose) by using a frequently sampled oral glucose tolerance test (OGTT) at 15 and 35 weeks' gestation in women with overweight or obesity who had GDM (n = 29) or did not have GDM (No-GDM; n = 164) at 35 weeks.At 15 weeks, IS and β-cell function were lower, and fasting, 1-h, and total area-under-the-curve plasma glucose concentrations during the OGTT were higher (all P < 0.05) in the GDM than in the No-GDM group. At 35 weeks compared with 15 weeks, IS decreased, β-cell function increased, and postprandial suppression of plasma FFA was blunted in both the GDM and No-GDM groups, but the decrease in IS and the increase in postprandial FFA concentration were greater and the increase in β-cell function was less (all P ≤ 0.05) in the GDM than in the No-GDM group. A receiver operating characteristic curve analysis showed that both fasting plasma glucose and 1-h OGTT glucose concentration at 15 weeks are predictors of GDM, but the predictive power was <30%.Women with overweight or obesity and GDM, compared with those without GDM, have worse IS and β-cell function early during pregnancy and a greater subsequent decline in IS and blunted increase in β-cell function. Increased fasting and 1-h OGTT plasma glucose concentration early during pregnancy are markers of increased GDM risk, albeit with weak predictive power.
Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma
Authors: Raj K. Gopal, Venkata R. Vantaku, Apekshya Panda, Bryn Reimer, Sneha Rath, Tsz-Leung To, Adam S. Fisch, Murat Cetinbas, Maia Livneh, Michael J. Calcaterra, Benjamin J. Gigliotti, Kerry A. Pierce, Clary B. Clish, Dora Dias-Santagata, Peter M. Sadow, Lori J. Wirth, Gilbert H. Daniels, Ruslan I. Sadreyev, Sarah E. Calvo, Sareh Parangi, Vamsi K. Mootha
Journal: Cancer Discovery (2023)

Abstract Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC. A CRISPR–Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against lipid peroxides and ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity. Significance: HCC harbors abundant mitochondria, mitochondrial DNA mutations, and chromosomal losses. Using a CRISPR–Cas9 screen inspired by transcriptomic and metabolomic profiling, we identify molecular effectors essential for cell fitness. We uncover lipid peroxide stress as a vulnerability coupled to mitochondrial complex I loss in HCC. See related article by Frank et al., p. 1884. This article is highlighted in the In This Issue feature, p. 1749
Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hürthle Cell Carcinoma of the Thyroid
Authors: Anderson R. Frank, Vicky Li, Spencer D. Shelton, Jiwoong Kim, Gordon M. Stott, Leonard M. Neckers, Yang Xie, Noelle S. Williams, Prashant Mishra, David G. McFadden
Journal: Cancer Discovery (2023)

Abstract A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hürthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR–Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I–mutant HTC cells. We demonstrate in cultured cells and a patient-derived xenograft model that small-molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration. Significance: HTC is enriched in somatic mtDNA mutations predicted to affect complex I of the electron transport chain (ETC). We demonstrate that these mutations impair respiration and induce a therapeutically tractable reliance on aerobic fermentation for cell survival. This work provides a rationale for targeting fermentation in cancers harboring irreversible genetically encoded ETC defects. See related article by Gopal et al., p. 1904. This article is highlighted in the In This Issue feature, p. 1749
Ethical Responsibilities for Companies That Process Personal Data
Authors: Matthew S. McCoy, Anita L. Allen, Katharina Kopp, Michelle M. Mello, D. J. Patil, Pilar Ossorio, Steven Joffe, Ezekiel J. Emanuel
Journal: The American Journal of Bioethics (2023)

It has become increasingly difficult for individuals to exercise meaningful control over the personal data they disclose to companies or to understand and track the ways in which that data is exchanged and used. These developments have led to an emerging consensus that existing privacy and data protection laws offer individuals insufficient protections against harms stemming from current data practices. However, an effective and ethically justified way forward remains elusive. To inform policy in this area, we propose the Ethical Data Practices framework. The framework outlines six principles relevant to the collection and use of personal data-minimizing harm, fairly distributing benefits and burdens, respecting autonomy, transparency, accountability, and inclusion-and translates these principles into action-guiding practical imperatives for companies that process personal data. In addition to informing policy, the practical imperatives can be voluntarily adopted by companies to promote ethical data practices.
Re: Ziad Bakouny, Talal El Zarif, Shaan Dudani, et al. Upfront Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy: An Observational Study from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol 2023;83:145–51
Authors: Jinze Li, Bo Chen, Dehong Cao
Journal: European Urology (2023)
Clinical Image: Delta phalanx (longitudinally bracketed epiphysis)
Authors: Daphne J. Theodorou, Stavroula J. Theodorou, Niki D. Tsifetaki
Journal: Arthritis & Rheumatology (2023)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Understanding the effectiveness of different exercise training programme designs on V̇O<sub>2peak</sub>in COPD: a component network meta-analysis
Authors: Thomas JC Ward, Charles D Plumptre, Alessandra V Fraser-Pye, Thomas E Dolmage, Amy V Jones, Ruth Trethewey, Lorna Latimer, Sally J Singh, Martin R Lindley, Michael C Steiner, Rachael A Evans
Journal: Thorax (2023)

Pulmonary rehabilitation programmes including aerobic training improve cardiorespiratory fitness in patients with COPD, but the optimal programme design is unclear. We used random effects additive component network meta-analysis to investigate the relative effectiveness of different programme components on fitness measured by V̇O 2peak in COPD. The included 59 studies involving 2191 participants demonstrated that V̇O 2peak increased after aerobic training of at least moderate intensity with the greatest improvement seen following high intensity training. Lower limb aerobic training (SMD 0.56 95% CI 0.32;0.81, intervention arms=86) and the addition of non-invasive ventilation (SMD 0.55 95% CI 0.04;1.06, intervention arms=4) appeared to offer additional benefit but there was limited evidence for effectiveness of other exercise and non-exercise components.
Performance and symmetry measures during vertical jump testing at return to sport after ACL reconstruction
Authors: Roula Kotsifaki, Vasileios Sideris, Enda King, Roald Bahr, Rod Whiteley
Journal: British Journal of Sports Medicine (2023)

Vertical jump tests are more sensitive in revealing asymmetries in performance metrics at the time of return to sport after anterior cruciate ligament (ACL) reconstruction (ACLR) than horizontal hop tests. However, it remains unclear which vertical tests (bilateral or unilateral) and which metrics (kinetics or performance) are most effective in informing the rehabilitation status and readiness for return to sport. We aimed to investigate the status of athletes during vertical jump testing at return to sport after ACLR.A dual force platform system was used to evaluate jumping performance of 126 recreational and professional athletes at the time of return to sport after ACLR, as well as 532 healthy control participants. Performance and kinetic metrics were collected during four jump tests: double-leg countermovement jump, single-leg countermovement jump, double-leg 30 cm drop jump and single-leg 15 cm drop jump. Between-limb and between-group differences were explored using mixed models analyses.At the time of return to sport after ACLR, athletes still presented significant differences favouring the uninvolved side, particularly in the symmetry of the concentric impulse (p<0.001) in all jumps compared with the control group. Peak landing force asymmetry was greater in the ACLR group than the controls during the countermovement (p<0.001, MD=-11.6; 95% CI -15.4 to -7.9) and the double-leg drop jump (p=0.023, MD=-8.9; 95% CI -14.9 to -2.8). The eccentric impulse asymmetry was significantly greater (p=0.018, MD=-3.8; 95% CI -5.8 to -1.7) in the ACLR group during the single-leg drop jump only. Jump height was significantly lower (p<0001) in the ACLR group compared with controls in all tests except the double-leg drop jump.At the time of return to sport after ACLR, despite passing the traditional discharge criteria, athletes remained asymmetrical during all vertical jump tests, in the concentric (push-off) phase, during landing from bilateral jumps and for most performance metrics. Clinicians should aim to restore not only symmetry in ground reaction forces but also absolute performance metrics such as jump height, reactive strength index and contact times, to potentially reduce injury risk and improve overall athletic performance.
Is methotrexate safe for men with an immune-mediated inflammatory disease and an active desire to become a father? Results of a prospective cohort study (iFAME-MTX)
Authors: Luis Fernando Perez-Garcia, Esther Röder, Bouwe P Krijthe, Laura JC Kranenburg-van Koppen, Roxanne van Adrichem, Els Zirkzee, Pieter H Griffioen, Kris Peeters, Marry Lin, Eduard A Struys, Gerrit Jansen, Martijn BA van Doorn, Robert de Jonge, Gert R Dohle, Radboud JEM Dolhain
Journal: Annals of the Rheumatic Diseases (2023)

Current scientific evidence guiding the decision whether men with an active desire to become a father should be treated with methotrexate (MTX) remains controversial. We aimed to prospectively evaluate the testicular toxicity profile of MTX focusing on several markers of male fertility, including semen parameters and sperm DNA fragmentation index (sDFI). As a secondary outcome, we aimed to evaluate whether MTX-polyglutamates can be detected in spermatozoa and seminal plasma and to evaluate the enzymatic activity in spermatozoa of folylpolyglutamate synthetase (FPGS).In a prospective cohort study, men ≥18 years who started therapy with MTX were invited to participate (MTX-starters). Participants were instructed to produce two semen samples (a pre-exposure and a post-exposure sample after 13 weeks). Healthy men ≥18 years were invited to participate as controls. Conventional semen analyses, male reproductive endocrine axis and sDFI were compared between groups. FPGS enzymatic activity and MTX-PG1-5 concentrations were determined by mass spectrometry analytical methods.In total, 20 MTX-starters and 25 controls were included. The pre-exposure and postexposure semen parameters of MTX-starters were not statistically significant different. Compared with healthy controls, the conventional semen parameters and the sDFI of MTX-starters were not statistically significant different. These data were corroborated by the marginal accumulation of MTX-PGs in spermatozoa, consistent with the very low FPGS enzymatic activity associated with the expression of an alternative FPGS splice-variant.Treatment with MTX is not associated with testicular toxicity, consistent with the very low concentration of intracellular MTX-PG. Therefore, therapy with MTX can be safely started or continued in men and with a wish to become a father.
Directions of change in intrinsic case severity across successive SARS-CoV-2 variant waves have been inconsistent
Authors: David J. Pascall, Elen Vink, Rachel Blacow, Naomi Bulteel, Alasdair Campbell, Robyn Campbell, Sarah Clifford, Chris Davis, Ana da Silva Filipe, Noha El Sakka, Ludmila Fjodorova, Ruth Forrest, Emily Goldstein, Rory Gunson, John Haughney, Matthew T.G. Holden, Patrick Honour, Joseph Hughes, Edward James, Tim Lewis, Oscar MacLean, Martin McHugh, Guy Mollett, Tommy Nyberg, Yusuke Onishi, Ben Parcell, Surajit Ray, David L. Robertson, Shaun R. Seaman, Sharif Shabaan, James G. Shepherd, Katherine Smollett, Kate Templeton, Elizabeth Wastnedge, Craig Wilkie, Thomas Williams, Emma C. Thomson
Journal: Journal of Infection (2023)

ObjectivesTo determine how the intrinsic severity of successively dominant SARS-CoV-2 variants changed over the course of the pandemic.MethodsA retrospective cohort analysis in the NHS Greater Glasgow and Clyde (NHS GGC) Health Board. All sequenced non-nosocomial adult COVID-19 cases in NHS GGC with relevant SARS-CoV-2 lineages (B.1.177/Alpha, Alpha/Delta, AY.4.2 Delta/non-AY.4.2 Delta, non-AY.4.2 Delta/Omicron, and BA.1 Omicron/BA.2 Omicron) during analysis periods were included. Outcome measures were hospital admission, ICU admission, or death within 28 days of positive COVID-19 test. We report the cumulative odds ratio; the ratio of the odds that an individual experiences a severity event of a given level vs all lower severity levels for the resident and the replacement variant after adjustment.ResultsAfter adjustment for covariates, the cumulative odds ratio was 1.51 (95% CI: 1.08-2.11) for Alpha versus B.1.177, 2.09 (95% CI: 1.42-3.08) for Delta versus Alpha, 0.99 (95% CI: 0.76-1.27) for AY.4.2 Delta versus non-AY.4.2 Delta, 0.49 (95% CI: 0.22-1.06) for Omicron versus non-AY.4.2 Delta, and 0.86 (95% CI: 0.68-1.09) for BA.2 Omicron versus BA.1 Omicron.ConclusionsThe direction of change in intrinsic severity between successively emerging SARS-CoV-2 variants was inconsistent, reminding us that the intrinsic severity of future SARS-CoV-2 variants remains uncertain.
Nontumor Cells Possibly Cause Bias to the Evaluation of Gene Expression Score
Authors: Qihai Sui, Zhengyang Hu, Zhencong Chen, Cheng Zhan
Journal: Journal of Clinical Oncology (2023)

Evaluation of the Sensitivity to Endocrine Therapy Index and 21-Gene Breast Recurrence Score (RS) in the SWOG S8814 Trial."We really appreciate the insightful observation for their conclusion that SET2,3 index was not correlated with RS.However, after reading this article, we would like to express our concerns about the important issues it raises.In this article, SET2,3 indices were calibrated and measured using whole-transcriptome RNA sequences from tumor samples that had been used for RS testing.The primary end point was disease-free survival.Traditional microarray and RNA sequencing technologies, in fact, are primarily concerned with the average expression of all cells in a sample.Tumor cells, on the other hand, are only one component of tumor samples, which also contain a large number of matrix cells and immune cells.Matrix cells and immune cells form the tumor microenvironment, which not only promotes the development of tumor but also contributes to therapy resistance. 2 Previous studies suggested that the complexity and heterogeneity in the tumor microenvironment hampered the efficacy of breast cancer treatment. 3
Reply to Y. Wang et al and Q. Sui et al
Authors: Nathalie LeVasseur, Karen A. Gelmon
Journal: Journal of Clinical Oncology (2023)

Speers et al 3 on the validation of SET2,3 in the SWOG S8814 clinical trial.They raise an interesting point about the potential clinical utility of combining SET2,3 with the Oncotype DX recurrence score (RS) to consider omitting radiotherapy for selected patients with a favorable prognosis, to mitigate treatment-related toxicity.
ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer
Authors: P. Tarantino, G. Viale, M.F. Press, X. Hu, F. Penault-Llorca, A. Bardia, A. Batistatou, H.J. Burstein, L.A. Carey, J. Cortes, C. Denkert, V. Diéras, W. Jacot, A.K. Koutras, A. Lebeau, S. Loibl, S. Modi, M.F. Mosele, E. Provenzano, G. Pruneri, J.S. Reis-Filho, F. Rojo, R. Salgado, P. Schmid, S.J. Schnitt, S.M. Tolaney, D. Trapani, A. Vincent-Salomon, A.C. Wolff, G. Pentheroudakis, F. André, G. Curigliano
Journal: Annals of Oncology (2023)
Comparative Risks of Infection With Belimumab Versus Oral Immunosuppressants in Patients With Nonrenal Systemic Lupus Erythematosus
Authors: Emma Materne, Hyon Choi, Baijun Zhou, Karen H. Costenbader, Yuqing Zhang, April Jorge
Journal: Arthritis & Rheumatology (2023)

Objective We investigated the comparative risk of infection with belimumab versus oral immunosuppressants for the treatment of systemic lupus erythematosus (SLE). Methods Using observational data from a US multicenter electronic health record database, we identified patients with SLE but without lupus nephritis who initiated belimumab, azathioprine, methotrexate, or mycophenolate between 2011 and 2021. We designed and emulated hypothetical target trials to estimate the cumulative incidence and hazard ratios (HRs) of serious infection and hospitalization for serious infection comparing belimumab versus each oral immunosuppressant. We used propensity score overlap weighting to balance baseline covariates and adjusted for adherence to treatment group using inverse probability of treatment weighting. We also assessed the control outcome of traumatic injury. Results Among 21,481 patients, we compared 2841 and 6343 initiators of belimumab and azathioprine, 2642 and 8242 initiators of belimumab and methotrexate, and 2813 and 8407 initiators of belimumab and mycophenolate, respectively. After propensity score overlap weighting, all covariates were balanced in each comparison. The mean age of the cohort was 45 years, and 94% were women. Compared with azathioprine and mycophenolate, belimumab was associated with lower risks of both serious infection (HR 0.82; 95% confidence interval [CI] 0.72–0.92 and HR 0.69; 95% CI 0.61–0.78) and hospitalization for infection (HR 0.73; 95% CI 0.57–0.94 and HR 0.56 95% CI 0.43–0.71). The risk of infection was also lower for belimumab compared with methotrexate (HR 0.86; 95% CI 0.76–0.97). There were no differences in traumatic injury risks across treatment groups. Conclusion Belimumab was associated with lower risks of serious infection than with oral immunosuppressants. This finding should inform risk/benefit considerations for SLE treatment. image
Could Adjuvant Radiotherapy Be Avoided for Postmenopausal Patients With Node-Positive Estrogen Receptor–Positive Breast Cancer and Favorable Recurrence Score and SET2,3 Scores?
Authors: Yanhong Wang, Qunrong Cai
Journal: Journal of Clinical Oncology (2023)

We write regarding the recent article by Speers et al 1 which found that both 21-Gene Breast Recurrence Score (RS) and sensitivity to endocrine therapy (SET2,3) index offered independently prognostic information for postmenopausal patients with node-positive estrogen receptor-positive breast cancer, and patients with RS ≤ 25 and high SET2,3 had 5-year disease-free survival of 97% in overall study population and in the subset treated with tamoxifen alone.We would like to congratulate the authors for their efforts in performing this study.